Gerald Alter (Other), Steven J. Berberich (Committee Member), Thomas L Brown (Committee Member), Madhavi Kadakia (Advisor), Michael Leffak (Committee Member), James Mcdougal (Committee Member), Joseph F. Thomas, Jr. (Other)
Doctor of Philosophy (PhD)
The tumor suppressor p53 is the single most altered gene in human cancers. p53 homologues, p63 and p73 play a major role in development and in human cancer. Both p63and p73-null mice exhibit profound developmental abnormalities, suggesting a vital role for p63 and p73 in development. Although the role of p73 in human cancers is well established, the role of p63 still remains to be understood. While p63 plays a major role in development, p73 plays a major role in tumor suppression as well as in development. Although a functional co-operation is evident between each member of p53 family, additional studies are required to understand the functional cross-talk between each member of the p53 family, and their ability to govern multiple biological functions. Identifying common and specific transcriptional networks of p53 family is essential for understanding the existing functional co-operation between each member.
This dissertation focuses on defining the functional relevance of the regulation of vitamin D receptor (VDR) by p53 family members. Secosteroid hormone vitamin D, through its cognate receptor VDR, regulates genes involved in mineral homeostasis, bone formation and in epidermal differentiation. Vitamin D and its analogues also exhibit anti- proliferative activities and are widely used as cancer chemotherapeutic agents. Findings from this study demonstrated VDR as a direct target of p63 and p73; however p53 does not appear to regulate VDR directly or indirectly. One part of this dissertation underpinned the role of VDR in p63 mediated biological functions. Down regulation of endogenous p63 in human epidermoid cancer cells resulted in complete loss of endogenous VDR expression. In addition, up-regulation of VDR by p63 appears to inhibit the migration and invasion of human epidermoid cancer cells. the second part of this dissertation is involved in understanding the p73 mediated regulation of VDR in vitamin D-mediated differentiation. Findings from this section of study demonstrated that DNA damage-induced expression of VDR is dependent on p73. In addition, p73 was proven to be essential for vitamin D mediated osteoblastic differentiation. Furthermore, we demonstrated that DNA damage sensitized the cells to vitamin D mediated differentiation through p73. Taken together, while understanding the regulation of VDR by p63 will provide new insights on the molecular mechanisms of p63 biology, determining the role of p73 in vitamin D-mediated differentiation may aid in vitamin D based cancer chemotherapeutics.
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